Cutaneous malignant melanoma, already notorious for its highly aggressive behavior and its resistance to currently available therapies, has evolved into a true health crisis by virtue of an alarming elevation in incidence. Recent studies have provided compelling evidence for a significant underlying genetic basis for melanoma, as well as a causal role for sunlight exposure in its etiology. However, the functional relationship between genes and environment in the pathogenesis of melanoma is virtually unknown. Retrospective epidemiological data currently suggest that, unlike other skin cancers which are associated with cumulative lifetime ultraviolet (UV) exposure, melanoma is provoked by intense intermittent exposure to UV, particularly during childhood. We have directly tested this hypothesis in mice harboring a transgene encoding hepatocyte growth factor/scatter factor (HGF/SF), the ligand of the c-Met receptor tyrosine kinase. HGF/SF induces the formation of extra-follicular melanocytes, akin to human skin, and sporadic melanocytic tumors in aged animals. We have reported (Noonan et al., 2000) that chronic adult suberythemal (non-reddening) UV irradiation failed to accelerate melanomagenesis in HGF/SF-transgenic mice. In contrast, we have now determined that a single neonatal dose of erythemal UV radiation is necessary and sufficient to induce cutaneous melanoma with high penetrance, arising with histopathologic and molecular pathogenetic profiles reminiscent of human melanoma (Noonan et al., in press). These data provide the first experimental support of epidemiological evidence that childhood sunburn poses a highly significant risk for this escalating, deadly disease. Moreover, this model provides an experimental platform anticipated to facilitate the establishment of more effective sun protection strategies, assessment of the role of suspected human genetic risk factors and development of efficacious therapies. The childhood skeletal muscle malignancy, rhabdomyosarcoma (RMS), is thought to arise from imbalances in myogenic proliferation and differentiation, processes that are normally controlled by growth factor signaling pathways linked to key effectors of myogenesis and the cell cycle. However, except for the signature balanced reciprocal PAX3/FKHR translocation, the pathways regulating the development of RMS remain largely unknown. This is due, at least in part, to the lack of an RMS-prone mouse model. In the process of determining the consequences of ink4a deficiency in the melanoma model described above, we discovered that virtually all ink4a mutant mice that ectopically express HGF/SF selectively succumbed at a mean onset age of 3 months to highly invasive, multicentric RMS. As in humans, these aggressive tumors arose at both skeletal and nonskeletal muscle sites. Moreover, analogous pathway alterations were also detected in a panel of primary human RMS samples. Our data suggest that c-MET and INK4a/ARF pathways represent critical, synergistic targets in RMS pathogenesis. c-MET has been implicated in human tumorigenesis through mutational activation, amplification/overexpression, and acquisition of cell-autonomous autocrine signaling loops via co-expression of HGF/SF. HGF/SF possesses an impressive array of biological activities, many able to facilitate tumor cell metastasis, including induction of cellular growth, motility and invasiveness. Previously, we reported the potential of transgenic mice broadly expressing either HGF/SF to serve as host for intravenous transplantation (Otsuka et al., 2000). We have now employed a combination of genetically engineered cell lines and genetically engineered host mice to directly compare the contribution of paracrine- and autocrine-mediated c-Met signaling to metastatic colonization in vivo (Yu and Merlino, MS in preparation). We found that metastatic efficiency under non-cell autonomous conditions (i.e., where tumor cells expressed c-Met and HGF/SF was produced exclusively by transgenic host tissue) was at least as high as under conditions of cell autonomous growth (i.e., HGF/SF-Met autocrine signaling). Moreover, the creation of an HGF/SF-Met autocrine loop in melanoma cells failed to improve their metastatic yield in HGF/SFtransgenic hosts. Our data demonstrate that growth factors not intrinsic to malignant cells can have a profound effect on metastatic efficiency in vivo, and provide experimental support implicating stromal-derived factors in tumor progression.